Medicinal anti-coagulation therapy has the risk of causing life-threatening bleeding events. Therefore, anti-coagulation therapy is regularly monitored to obtain the right balance between thrombosis and bleeding risk. The diagnostic test that is best used for this purpose depends on the type of anticoagulant drug that is administered. For short term anti-coagulation therapy that needs fast adjustments, unfractionated heparin, or heparin-like drugs such as low-molecular weight heparin (LMWH) and pentasaccharides are used. For longer term therapy, oral, vitamin K antagonist (VKA) type anticoagulants are most widely used. Approximately 1 to 2 out of every 100 people living in the western world uses VKAs.
VKA and heparin-like compounds have different modes of action. Heparin increases the function of anti-thrombin to inhibit mainly both F10a and thrombin. Heparin also inhibits also other active proteins such as F11a, F9a, F3-F7a, however their main mode of action is inhibition of F10a and thrombin. LMWH and the synthetic pentasaccharides may be more specific to F10a. The VKAs may inhibit the concentrations of functional thrombin, F7, F9, F10 protein C, protein S and protein Z. The most used test for heparin therapy is the activated partial thromboplastin time (aPTT), while the anti-Factor 10a assay is generally used to monitor LMWH or synthetic pentasaccharide type of drugs. Vitamin K antagonist therapy is traditionally monitored using the prothrombin time (PT), or its standardized derivative, the international normalized ratio (INR).
During certain situations however, for example after the acute phase of thrombosis treatment, or when a patient on vitamin K antagonists needs to undergo surgery, the therapy needs to change from one type of drug to another, also known as bridge or bridging therapy. Annually an estimated total of 250.000 patients need interruption of their VKA treatment in North America alone. This does not take into account all patients that start Warfarin treatment after an initial treatment with heparin. It is estimated that about 2 mln persons start Warfarin treatment each year. However, not all of these patients may have had an initial heparin treatment.
The action of VKA only slowly increases (transition from heparin-like drug to VKA) and also only decreases slowly (transition from VKA to heparin-like drug) due to an indirect effect on the production of the coagulation proteins.
There is not a test available that encapsulates the combined effect of both therapies. Furthermore, the tests used to measure the effect of a single therapy, e.g. aPTT or INR, are affected by the other therapy. VKA action only slowly increases and decreases due to its indirect effect on the coagulation proteins, and during this therapy, their partial anti-coagulation needs to be compensated for by the fast-acting heparin-like drugs to keep the patient in the correct hemostatic balance.
The physician has several options to monitor the hemostatic balance of the patient during the bridging period. First, the PT or INR can be used to monitor the patient during the bridging period. However, since the PT/INR is relatively insensitive to the effects of the heparin like drugs, targeting a constant value for this test will easily lead to overcompensation of the coagulation and an unacceptable high risk of bleeding. Similarly for the second option, using the aPTT to monitor the anti-coagulation, the aPTT is somewhat sensitive to the anti-coagulant effect of the VKAs but is certainly not optimized to monitor VKA therapy, thus targeting a constant value for this test will also easily lead to over-anti-coagulation and an unacceptable high risk of bleeding. In practice, physicians are known to opt for the third possibility: refrain from monitoring at all, but follow the (recommended) bridging guidelines, which are known to often lead to over-anti-coagulation.